US5717100AExpiredUtility
Substituted imidazoles having anti-cancer and cytokine inhibitory activity
Est. expiryOct 6, 2015(expired)· nominal 20-yr term from priority
C07D 417/14C07D 401/14
97
PatentIndex Score
116
Cited by
11
References
33
Claims
Abstract
Compounds represented by formula I: <IMAGE> I are disclosed. AR represents an aromatic group containing 6-10 atoms; and <IMAGE> represents a 4 to 6 membered non-aromatic heterocycle containing only one N atom. A pharmaceutical composition is also included. Methods of treating cancer and cytokine mediated diseases are also included.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound represented by formula I: ##STR93## or a pharmaceutically acceptable salt thereof, wherein: AR represents an aromatic group containing 6-10 atoms; X and X' each independently represent --(CH 2 ) m --Y--(CH 2 ) n --, wherein m and n represent integers within the range of from 0-4, such that the sum of m and n is from 0-6; Y represents a member selected from the group consisting of: a direct bond; O; S(O) y , with y equal to 0, 1 or 2; NR q' , with R q' as defined below; C(O); OC(O); C(O)O; SO x NR q' with x equal to 1 or 2 and R q' as defined below; NR q' SO x ; C(O)NR q' and NR q' C(O); ##STR94## represents a 4 to 6 membered non-aromatic heterocycle containing only N atom; R x represents H, C 1-6 alkyl(R q ) 3 , OC 1-6 alkyl(R q ) 3 or C(O)C 1-6 alkyl(R q ) 3 ; each R and R" independently represents a member selected from the group consisting of: halo; hydroxy; C 1-6 alkyl(R q ) 3 ; OC 1-6 alkyl(R q ) 3 ; C 3-8 cycloalkyl(R q ) 3 ; CN; CONH 2 ; CONHC 1-6 alkyl(R q ) 3 ; CON(C 1-6 alkyl(R q ) 3 ) 2 ; NH 2 ; NHC 1-6 alkyl(R q ) 3 ; N(C 1-6 alkyl(R q ) 3 ) 2 ; CO 2 H; CO 2 C 1-6 alkyl(R q ) 3 ; C(O)C 1-6 alkyl(R q ) 3 ; aryl(R q ) 3 ; heteroaryl(R q ) 3 ; CF 3 ; SH; NO 2 ; SO y C 1-6 alkyl(R q ) 3 , with y as defined above; SO 2 NH 2 ; SO 2 NHC 1-6 alkyl(R q ) 3 ; SO 2 N(C 1-6 alkyl(R q ) 3 ) 2 ; NHSO 2 C 1-6 alkyl(R q ) 3 , NHSO 2 aryl(R q ) 3 , NHSO 2 heteroary(R q ) 3 , N(R q' )C(O)C 1-6 alkyl(R q ) 3 ; NR q' C(O)NH(C 1-6 alkyl(R q ) 3 ); C 2-4 alkenyl(R q ) 2-3 and C 2-4 alkynyl(R q ) 1-3 ; each R' independently represents a member selected from the group consisting of: hydroxy; C 1-6 alkyl(R q ) 3 ; C 3-8 cycloalkyl(R q ) 3 ; OC 1-6 alkyl(R q ) 3 ; OC 3-8 cycloalkyl(R q ) 3 ; heterocyclyl(R q ) 3 ; CN; NH(R q" ); NHC 1-6 alkyl(R q ) 3 ; N(C 1-6 alkyl(R q ) 3 ) 2 ; NHC 3-8 cycloalkyl(R q ) 3 ; N(C 3-8 cycloalkyl(R q ) 3 ) 2 ; CF 3 ; SH; NO 2 ; C 2-4 alkenyl(R q ) 2-3 , aryl(R q ) 3 , heteroaryl(R q ) 3 ; C 2-4 alkynyl(R q ) 1-3 ; --OC(O)C 3-8 cycloalkyl(R q ) 3 ; SO 2 NH 2 ; SO 2 NHC 1-6 alkyl(R q ) 3 ; SO 2 N(C 1-6 alkyl(R q ) 3 ) 2 ; NHSO 2 C 1-6 alkyl(R q ) 3 , NHSO 2 aryl(R q ) 3 , NHSO 2 heteroary(R q ) 3 , --OC(O)heterocyclyl(R q ) 3 ; N(R q' )C(O)C 1-6 alkyl(R q ) 3 ; NR q' C(O)NH(C 1-6 alkyl(R q ) 3 ); --OC(O)C 1-6 alkyl(R q ) 3 ; --OC(O)aryl(R q ) 3 , --OC(O)heteroaryl(R q ) 3 ; --C(═NR q' )NH 2 ; --C(═N q' )NHC 1-6 alkyl(R q ) 3 , --C(═N q' )N(C 1-6 alkyl(R q ) 3 ) 2 ; CONH 2 ; CONHC 1-6 alkyl(R q ) 3 ; CON(C 1-6 alkyl(R q ) 3 ) 2 ; CONHC 3-8 cycloalkyl(R q ) 3 ; CON(C 3-8 cycloalkyl(R q ) 3 ) 2 ; CO 2 H; CO 2 C 1-6 alkyl(R q ) 3 ; C(O)C 1-6 alkyl(R q ) 3 ; CO 2 C 3-8 cycloalkyl(R q ) 3 ; C(O)C 3-8 cycloalkyl(R q ) 3 ; -- C(O)(CH 2 ) j --CR 5 R 6 --(CH 2 ) k --NR 7 ! p--R 8 ; --C(O)C 3-8 cycloalkyl(R q ) 3 ; --C(O)heterocyclyl(R q ) 3 ; --CON C 1-6 alkyl(R q ) 3 ! C 3-8 cycloalkyl(R q ) 3 !; --C(O)aryl(R q ) 3 , --C(O)heteroaryl(R q ) 3 ; ##STR95## j and k independently represent integers of from 0-3; R 5 and R 6 are independently H, aryl, C 1-6 alkyl(R q ) 3 , or CR 5 R 6 in combination represents a 3, 4, 5 or 6 membered cycloalkyl or heterocyclyl group, an aryl group or a heteroaryl group; p represents 1, 2 or 3, with the proviso that when p represents 1, CR 5 R 6 represents a 3, 4, 5 or 6 membered cycloalkyl group or a heterocyclyl group, an aryl group or a heteroaryl group, and at least one of j and k is 1, 2 or 3; R 7 and R 8 are independently H, C 1-6 alkyl or aryl; R 9 represents H, a negative charge balanced by a positively charged group or a protecting group; R q represents a member selected from the group consisting of: R q' ; CN; CO 2 H; CO 2 C 1-4 alkyl; C(O)C 1-4 alkyl; NH(R q" ); aryl(R a ) 3 ; heteroaryl(R a ) 3 ; NHC 1-4 alkyl; N(C 1-4 alkyl) 2 ; CONH 2 ; SH; S(O) y C 1-6 alkyl(R a ) 3 ; C(O)NHC 1-6 alkyl(R a ) 3 ; C(O)N(C 1-6 alkyl(R a ) 3 ) 2 ; NHC(NH)NH 2 ; -heteroalkyl(R a ) 3 ; --NHC(O)NH 2 ; ##STR96## wherein ##STR97## independently represent mono or bicyclic ring systems, non-aromatic or partially aromatic, containing from 5-10 ring atoms, 1-4 of which are N and 0-1 of which are O or S(O) y , with y equal to 0, 1 or 2, optionally containing 1-2 carbonyl groups; each R a independently represents a member selected from the group consisting of: H, C 1-6 alkyl, OC 1-6 alkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, aralkoxy, substituted aralkoxy, halo, hydroxy, CN, CONH 2 , CONHC 1-6 alkyl, CON(C 1-6 alkyl) 2 , CO 2 H, CO 2 C 1-6 alkyl, C(O)C 1-6 alkyl, phenyl, CF 3 , SH, NO 2 , SO y C 1-6 alkyl, with y as defined above; SO 2 NH 2 , SO 2 NHC 1-6 alkyl, NHSO 2 (substituted aryl), NHSO 2 (substituted heteroaryl), NHSO 2 C 1-6 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , NHC(O)C 1-6 alkyl, NHC(O)NH(C 1-6 alkyl), C 2-4 alkenyl and C 2-4 alkynyl; R q' represents H, OH, C 1-4 alkyl, --OC 1-4 alkyl, aryl or C(O)C 1-4 alkyl, and R q" represents H, OH or OC 1-4 alkyl.
2. A compound in accordance with claim 1 wherein one or two R" are present, each independently representing a member selected from the group consisting of: NH 2 , NHC 1-6 alkyl(R q ) 3 , N(C 1-6 alkyl) 2 , N(R q' )C(O)C 1-6 alkyl(R q ) 3 and NR q' C(O)NHC 1-6 alkyl(R q ) 3 .
3. A compound in accordance with claim 1 wherein AR represents a phenyl ring unsubstituted or substituted with one or two R groups.
4. A compound in accordance with claim 3 wherein AR is phenyl and one or two R groups are present which are selected from the group consisting of: hydroxyl, halo, C 1-6 alkyl(R q ) 3 , OC 1-6 alkyl(R q ) 3 , NH 2 , CF 3 and NO 2 .
5. A compound in accordance with claim 4 wherein each R represents halo, hydroxy or CF 3 .
6. A compound in accordance with claim 1 wherein: HETCy represents a 5-6 membered non-aromatic heterocycle with 1 nitrogen atom contained therein.
7. A compound in accordance with claim 1 wherein each R' is selected from the group consisting of: C 1-6 alkyl(R q ) 3 , OC 1-6 alkyl(R q ) 3 , CN and NO 2 .
8. A compound in accordance with claim 1 wherein R q is selected from R q' , CN, NH(R q" ) ##STR98## R q' represents H, C 1-4 alkyl, OH or aryl; R q" represents H or OH; ##STR99## represents a bicyclic partially aromatic group selected from phthalidyl and saccharinyl, and ##STR100## represents piperidinyl.
9. A compound in accordance with claim 1 wherein each R' represents a member selected from the group consisting of: --OC(O)C 3-8 cycloalkyl(R q ) 3 , --OC(O)heterocyclyl(R q ) 3 , N(R q' )C(O)C 1-6 alkyl(R q ) 3 , --N(R q' )C(O)NH(C 1-6 alkyl(R q ) 3 , --OC(O)C 1-6 alkyl(R q ) 3 , --OC(O)aryl(R q ) 3 , --OC(O)heteroaryl(R q ) 3 , --O C(O)(CH 2 ) j --CR 5 R 6 --(CH 2 ) k --NR 7 ! p R 8 , and -- NR 7 --(CH 2 ) k CR 5 R 6 --(CH 2 ) j --C(O)! p --OR 9 .
10. A compound in accordance with claim 9 wherein R q represents H, C 1-4 alkyl or OC 1-4 alkyl; R q" represents H or C 1-4 alkyl; p is 1 or 2; when p is 1, j represents 1 and k represents 0, 1 or 2; when p is 2, j represents 0 or 1, and k represents 0, 1 or 2; R 5 and R 6 represent H or C 1-6 alkyl(R q ) 3 or one of R 5 and R 6 represents aryl and the other is H or C 1-6 alkyl(R q ) 3 ; R 7 and R 8 represent H or C 1-6 alkyl(R q ) 3 , and R 9 represents H.
11. A compound in accordance with claim 1 wherein each R' represents a member selected from the group consisting of: CONH 2 ; CONHC 1-6 alkyl(R q ) 3 ; CON(C 1-6 alkyl(R q ) 3 ) 2 ; CONHC 3-8 cycloalkyl(R q ) 3 ; CON(C 3-8 cycloalkyl(R q ) 3 ) 2 ; CO 2 H; CO 2 C 1-6 alkyl(R q ) 3 ; C(O)C 1-6 alkyl(R q ) 3 ; CO 2 C 3-8 cycloalkyl(R q ) 3 ; C(O)C 3-8 cycloalkyl(R q ) 3 ; -- C(O)(CH 2 ) j --CR 5 R 6 --(CH 2 ) k --NR 7 ! p --R 8 ; --C(O)C 3-8 cycloalkyl(R q ) 3 ; --C(O)heterocyclyl(R q ) 3 ; CON C 1-6 alkyl(R q ) 3 ! C 3-8 cycloalkyl(R q ) 3 !; C(O)aryl(R q ) 3 and C(O)heteroaryl(R q ) 3 ; p represents 1, 2 or 3, and all other variables are as previously defined.
12. A compound in accordance with claim 1 wherein each R' independently represents a member selected from the group consisting of: CONH 2 ; CONHC 1-6 alkyl(R q ) 3 ; CON(C 1-6 alkyl(R q ) 3 ) 2 ; CO 2 H; CO 2 C 1-6 alkyl(R q ) 3 ; C(O)C 1-6 alkyl(R q ) 3 ; -- C(O)(CH 2 ) j --CR 5 R 6 --(CH 2 ) k --NR 7 ! p R 8 ; C(O)aryl(R q ) 3 and C(O)heteroaryl(R q ) 3 ; R q is R q' , CN, ##STR101## R q' represents H, C 1-4 alkyl, OH or aryl; ##STR102## represents a bicyclic partially aromatic group selected from phthalidyl and saccharinyl, and ##STR103## represents piperidinyl.
13. A compound in accordance with claim 12 wherein R' represents a member selected from the group consisting of: CONH 2 ; CO 2 H; CO 2 C 1-6 alkyl(R q ) 3 ; C(O)C 1-6 alkyl(R q ) 3 ; and -- C(O)(CH 2 ) j --CR 5 R 6 --(CH 2 ) k --NR 7 ! p R 8 ; R q represents H, C 1-4 alkyl or OC 1-4 alkyl; p represents 1; j represents 0 or 1; k represents 0, 1 or 2; and each R 7 and R 8 preferably represents H or C 1-6 6 alkyl(R q ) 3 .
14. A compound in accordance with claim 1 wherein R x is H or C 1-6 alkyl(R q ) 3 .
15. A compound in accordance with claim 1 wherein X' represents a direct bond.
16. A compound in accordance with claim 1 wherein X represents --(CH 2 ) m --Y--(CH 2 ) n --, Y represents a direct bond, O, S or C(O); m represents 0 or 1 and n represents 0 or 1.
17. A compound in accordance with claim 16 wherein X represents a direct bond.
18. A compound in accordance with claim 1 wherein: AR represents phenyl or naphthyl; X and X' represent --(CH 2 ) m --Y--(CH 2 ) n --, wherein m and n are zero and Y is a bond; HETCy represents a pyrrolidinyl or piperidinyl group; one or two R groups are present and are selected from the group consisting of: halo, hydroxy, C 1-6 alkyl(R q ) 3 , OC 1-6 alkyl(R q ) 3 , CN, NH 2 , CO 2 H, CF 3 , NO 2 and SO 2 NH 2 ; one or two R' groups are present and are selected from the group consisting of C 1-6 alkyl(R q ) 3 , OC 1-6 alkyl(R q ) 3 , CN and NO 2 ; R q represents R q' , CN, CO 2 H, NH(R q" ), ##STR104## R q' represents H, C 1-4 alkyl, OH or phenyl; R q" represents H or OH; ##STR105## represents phthalidyl or saccharinyl, and ##STR106## represents piperidinyl.
19. A compound in accordance with claim 1 wherein: AR represents an aromatic group containing 6-10 atoms; X and X' each independently represent --(CH 2 ) m --Y--(CH 2 ) n --, wherein m and n represent integers within the range of from 0-4, such that the sum of m and n is from 0-6; Y represents a member selected from the group consisting of: a direct bond; O; S(O) y , with y equal to 0, or 2; NR q' , with R q' as defined below; C(O); OC(O); C(O)O; SO x NR q' with x equal to 1 or 2 and R q' as defined below; NR q' SO x ; C(O)NR q' and NR q' C(O); ##STR107## represents a 4 to 6 membered non-aromatic heterocycle containing only one N atom; R x represents H, C 1-6 alkyl(R q ) 3 , OC 1-6 alkyl(R q )3 or C(O)C 1-6 alkyl(R q ) 3 ; each R independently represents a member selected from the group consisting of: halo; hydroxy; C 1-6 alkyl(R q ) 3 ; OC 1-6 alkyl(R q ) 3 ; C 3-8 cycloalkyl(R q ) 3 ; CN; CONH 2 ; CONHC 1-6 alkyl(R q ) 3 ; CON(C 1-6 alkyl(R q ) 3 ) 2 ; NH 2 ; NHC 1-6 alkyl(R q ) 3 ; N(C 1-6 alkyl(R q ) 3 ) 2 ; CO 2 H; CO 2 C 1-6 alkyl(R q ) 3 ; C(O)C 1-6 alkyl(R q ) 3 ; aryl(R q ) 3 ; heteroaryl(R q ) 3 ; CF 3 ; SH; NO 2 ; NHSO 2 C 1-6 alkyl(R q ) 3 , NHSO 2 aryl(R q ) 3 , NHSO 2 heteroary(R q ) 3 , N(R q' )C(O)C 1-6 alkyl(R q ) 3 ; NR q' C(O)NH(C 1-6 alkyl(R q ) 3 ); C 2-4 alkenyl(R q ) 2-3 and C 2-4 alkynyl(R q ) 1-3 ; each R" independently represents a member selected from the group consisting of: halo; hydroxy; C 1-6 alkyl(R q ) 3 ; OC 1-6 alkyl(R q ) 3 ; C 3-8 cycloalkyl(R q ) 3 ; CN; CONH 2 ; CONHC 1-6 alkyl(R q ) 3 ; CON(C 1-6 alkyl(R q ) 3 ) 2 ; NH 2 ; NHC 1-6 alkyl(R q ) 3 ; N(C 1-6 alkyl(R q ) 3 ) 2 ; CO 2 H; CO 2 C 1-6 alkyl(R q ) 3 ; C(O)C 1-6 alkyl(R q ) 3 ; aryl(R q ) 3 ; heteroaryl(R q ) 3 ; CF 3 ; SH; NO 2 ; SO y C 1-6 alkyl(R q ) 3 , with y as defined above; SO 2 NH 2 ; SO 2 NHC 1-6 alkyl(R q ) 3 ; SO 2 N(C 1-6 alkyl(R q ) 3 ) 2 ; NHSO 2 C 1-6 alkyl(R q ) 3 , NHSO 2 aryl(R q ) 3 , NHSO 2 heteroary(R q ) 3 , N(R q' )C(O)C 1-6 alkyl(R q ) 3 ; NR q' C(O)NH(C 1-6 alkyl(R q ) 3 ); C 2-4 alkenyl(R q ) 2-3 and C 2-4 alkynyl(R q ) 1-3 ; each R' independently represents a member selected from the group consisting of: hydroxy; C 1-6 alkyl(R q ) 3 ; C 3-8 cycloalkyl(R q ) 3 ; OC 1-6 alkyl(R q ) 3 ; OC 3-8 cycloalkyl(R q ) 3 ; heterocyclyl(R q ) 3 ; CN; NH(R q" ); NHC 1-6 alkyl(R q ) 3 ; N(C 1-6 alkyl(R q ) 3 ) 2 ; NHC 3-8 cycloalkyl(R q ) 3 ; N(C 3-8 cycloalkyl(R q ) 3 ) 2 ; CF 3 ; SH; NO 2 ; C 2-4 alkenyl(R q ) 2-3 , aryl(R q ) 3 , heteroaryl(R q ) 3 ; C 2-4 alkynyl(R q ) 1-3 ; --OC(O)C 3-8 cycloalkyl(R q ) 3 ; SO 2 NH 2 ; SO 2 NHC 1-6 alkyl(R q ) 3 ; SO 2 N(C 1-6 alkyl(R q ) 3 ) 2 ; NHSO 2 C 1-6 alkyl(R q ) 3 , NHSO 2 aryl(R q ) 3 , NHSO 2 heteroary(R q ) 3 , --OC(O)heterocyclyl(R q ) 3 ; N(R q' )C(O)C 1-6 alkyl(R q ) 3 ; NR q' C(O)NH(C 1-6 alkyl(R q ) 3 ); --OC(O)C 1-6 alkyl(R q ) 3 ; --OC(O)aryl(R q ) 3 , --OC(O)heteroaryl(R q ) 3 ; --C(═NR q' )NH 2 ; --C(═N q' )NHC 1-6 alkyl(R q ) 3 , --C(═N q' )N(C 1-6 alkyl(R q ) 3 ) 2 ; CONH 2 ; CONHC 1-6 alkyl(R q ) 3 ; CON(C 1-6 alkyl(R q ) 3 ) 2 ; CONHC 3-8 cycloalkyl(R q ) 3 ; CON(C 3-8 cycloalkyl(R q ) 3 ) 2 ; CO 2 H; CO 2 C 1-6 alkyl(R q ) 3 ; C(O)C 1-6 alkyl(R q ) 3 ; CO 2 C 3-8 cycloalkyl(R q ) 3 ; C(O)C 3-8 cycloalkyl(R q ) 3 ; -- C(O)(CH 2 ) j --CR 5 R 6 --(CH 2 ) k --NR 7 ! p --R 8 ; --C(O)C 3-8 cycloalkyl(R q ) 3 ; --C(O)heterocyclyl(R q ) 3 ; CON C 1-6 alkyl(R q ) 3 ! C 3-8 cycloalkyl(R q ) 3 !; C(O)aryl(R q ) 3 , C(O)heteroaryl(R q ) 3 ; ##STR108## j and k independently represent integers of from 0-3; R 5 and R 6 are independently H, aryl, C 1-6 alkyl(R q ) 3 , or CR 5 R 6 in combination represents a 3, 4, 5 or 6 membered cycloalkyl or heterocyclyl group, an aryl group or a heteroaryl group; p represents 1, 2 or 3, with the proviso that when p represents 1, CR 5 R 6 represents a 3, 4, 5 or 6 membered cycloalkyl group or a heterocyclyl group, an aryl group or a heteroaryl group, and at least one of j and k is 1, 2 or 3; R 7 and R 8 are independently H, C 1-6 alkyl or aryl; R9 represents H, a negative charge balanced by a positively charged group or a protecting group; R q represents a member selected from the group consisting of: R q' ; CN; CO 2 H; CO 2 C 1-4 alkyl; C(O)C 1-4 alkyl; NH(R q" ); aryl(R a ) 3 ; heteroaryl(R a ) 3 ; NHC 1-4 alkyl; N(C 1-4 alkyl) 2 ; CONH 2 ; SH;S(O) y C 1-6 alkyl(R a ) 3 ; C(O)NHC 1-6 alkyl(R a ) 3 ; C(O)N(C 1-6 alkyl(R a ) 3 ) 2 ; NHC(NH)NH 2 ; -heteroalkyl(R a ) 3 ; --NHC(O)NH 2 ; ##STR109## wherein ##STR110## independently represent mono or bicyclic ring systems, non-aromatic or partially aromatic, containing from 5-10 ring atoms, 1-4 of which are N and 0-1 of which are O or S(O) y , with y equal to 0, 1 or 2, optionally containing 1-2 carbonyl groups; each R a independently represents a member selected from the group consisting of: H, C 1-6 alkyl, OC 1-6 alkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, aralkoxy, substituted aralkoxy, halo, hydroxy, CN, CONH 2 , CONHC 1-6 alkyl, CON(C 1-6 alkyl) 2 , CO 2 H, CO 2 C 1-6 alkyl, C(O)C 1-6 alkyl, phenyl, CF 3 , SH, NO 2 , SO y C 1-6 alkyl, with y as defined above; SO 2 NH 2 , SO 2 NHC 1-6 alkyl, NHSO 2 (substituted aryl), NHSO 2 (substituted heteroaryl), NHSO 2 C 1-6 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , NHC(O)C 1-6 alkyl, NHC(O)NH(C 1-6 alkyl), C 2-4 alkenyl and C 2-4 alkynyl; R q' represents H, OH, C 1-4 alkyl, --OC 1-4 alkyl, aryl or C(O)C 1-4 alkyl, and R q" represents H, OH or OC 1-4 alkyl.
20. A compound in accordance with claim 19 wherein X represents a bond.
21. A compound represented by formula Ia: ##STR111## or a pharmaceutically acceptable salt thereof, wherein: X and X' each independently represent --(CH 2 ) m --Y--(CH 2 ) n --, wherein m and n represent integers within the range of from 0-4, such that the sum of m and n is from 0-6; Y represents a member selected from the group consisting of: a direct bond; O; S(O) y , with y equal to 0, 1 or 2; NR q' , with R q' as defined below; C(O); OC(O); C(O)O; SO x NR q' with x equal to 1 or 2 and R q' as defined below; NR q' SO x ; C(O)NR q' and NR q' C(O); R x represents H, C 1-6 alkyl(R q ) 3 or OC 1-6 alkyl(R q ) 3 ; each R independently represents a member selected from the group consisting of: halo; hydroxy; C 1-6 alkyl(R q ) 3 ; OC 1-6 alkyl(R q ) 3 ; C 3-8 cycloalkyl(R q ) 3 ; CN; CONH 2 ; CONHC 1-6 alkyl(R q ) 3 ; CON(C 1-6 alkyl(R q ) 3 ) 2 ; NH 2 ; NHC 1-6 alkyl(R q ) 3 ; N(C 1-6 alkyl(R q ) 3 ) 2 ; CO 2 H; CO 2 C 1-6 alkyl(R q ) 3 ; C(O)C 1-6 alkyl(R q ) 3 ; aryl(R q ) 3 ; heteroaryl(R q ) 3 ; CF 3 ; SH; NO 2 ; NHSO 2 C 1-6 alkyl(R q ) 3 , NHSO 2 aryl(R q ) 3 , NHSO 2 heteroary(R q ) 3 , N(R q' )C(O)C 1-6 alkyl(R q ) 3 ; NR q' C(O)NH(C 1-6 alkyl(R q ) 3 ); C 2-4 alkenyl(R q ) 2-3 and C 2-4 alkynyl(R q ) 1-3 ; each R" independently represents a member selected from the group consisting of: halo; hydroxy; C 1-6 alkyl(R q ) 3 ; OC 1-6 alkyl(R q ) 3 ; C 3-8 cycloalkyl(R q ) 3 ; CN; CONH 2 ; CONHC 1-6 alkyl(R q ) 3 ; CON(C 1-6 alkyl(R q ) 3 ) 2 ; NH 2 ; NHC 1-6 alkyl(R q ) 3 ; N(C 1-6 alkyl(R q ) 3 ) 2 ; CO 2 H; CO 2 C 1-6 alkyl(R q ) 3 ; C(O)C 1-6 alkyl(R q ) 3 ; aryl(R q ) 3 ; heteroaryl(R q ) 3 ; CF 3 ; SO y C 1-6 alkyl(R q ) 3 , with y as defined above; SO 2 NH 2 ; SO 2 NHC 1-6 alkyl(R q ) 3 ; SO 2 N(C 1-6 alkyl(R q ) 3 ) 2 ; NHSO 2 C 1-6 alkyl(R q ) 3 , NHSO 2 aryl(R q ) 3 , NHSO 2 heteroary(R q ) 3 , N(R q' )C(O)C 1-6 alkyl(R q ) 3 ; NR q' C(O)NH(C 1-6 alkyl(R q ) 3 ); C 2-4 alkenyl(R q ) 2-3 and C 2-4 alkynyl(R q ) 1-3 ; each R' independently represents a member selected from the group consisting of: hydroxy; C 1-6 alkyl(R q ) 3 ; C 3-8 cycloalkyl(R q ) 3 ; OC 1-6 alkyl(R q ) 3 ; OC 3-8 cycloalkyl(R q ) 3 ; heterocyclyl(R q ) 3 ; CN; NH(R q" ); NHC 1-6 alkyl(R q ) 3 ; N(C 1-6 alkyl(R q ) 3 ) 2 ; NHC 3-8 cycloalkyl(R q ) 3 ; N(C 3-8 cycloalkyl(R q ) 3 ) 2 ; CF 3 ; C 2-4 alkenyl(R q ) 2-3 , aryl(R q ) 3 , heteroaryl(R q ) 3 ; C 2-4 alkynyl(R q ) 1-3 ; --OC(O)C 3-8 cycloalkyl(R q ) 3 ; SO 2 NH 2 ; SO 2 NHC 1-6 alkyl(R q ) 3 ; SO 2 N(C 1-6 alkyl(R q ) 3 ) 2 ; --OC(O)heterocyclyl(R q ) 3 ; CONH 2 ; CONHC 1-6 alkyl(R q ) 3 ; CON(C 1-6 alkyl(R q ) 3 ) 2 ; CONHC 3-8 cycloalkyl(R q ) 3 ; CON(C 3-8 cycloalkyl(R q ) 3 ) 2 ; C(O)aryl(R q ) 3 , C(O)heteroaryl(R q ) 3 ; R q represents a member selected from the group consisting of: R q' ; CN; CO 2 H; CO 2 C 1-4 alkyl; C(O)C 1-4 alkyl; NH(R q" ); aryl(R a ) 3 ; heteroaryl(R a ) 3 ; NHC 1-4 alkyl; N(C 1-4 alkyl) 2 ; CONH 2 ; SH; S(O) y C 1-6 alkyl(R a ) 3 ; C(O)NHC 1-6 alkyl(R a ) 3 ; C(O)N(C 1-6 alkyl(R a ) 3 ) 2 ; NHC(NH)NH 2 ; -heteroalkyl(R a ) 3 ; --NHC(O)NH 2 ; ##STR112## wherein ##STR113## independently represent mono or bicyclic ring systems, non-aromatic or partially aromatic, containing from 5-10 ring atoms, 1-4 of which are N and 0-1 of which are O or S(O) y , with y equal to 0, 1 or 2, optionally containing 1-2 carbonyl groups; each R a independently represents a member selected from the group consisting of: H, C 1-6 alkyl, OC 1-6 alkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, aralkoxy, substituted aralkoxy, halo, hydroxy, CN, CONH 2 , CONHC 1-6 alkyl, CON(C 1-6 alkyl) 2 , CO 2 H, CO 2 C 1-6 alkyl, C(O)C 1-6 alkyl, phenyl, CF 3 , SH, NO 2 , SO y C 1-6 alkyl, with y as defined above; SO 2 NH 2 , SO 2 NHC 1-6 alkyl, NHSO 2 (substituted aryl), NHSO 2 (substituted heteroaryl), NHSO 2 C 1-6 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , NHC(O)C 1-6 alkyl, NHC(O)NH(C 1-6 alkyl), C 2-4 alkenyl and C 2-4 alkynyl; R q' represents H, OH, C 1-4 alkyl, --OC 1-4 alkyl, aryl or C(O)C 1-4 alkyl, and R q" represents H, OH or OC 1-4 alkyl.
22. A compound represented by formula Ib: ##STR114## or a pharmaceutically acceptable salt thereof, wherein: R x represents H, C 1-6 alkyl(R q ) 3 or OC 1-6 alkyl(R q ) 3 ; each R independently represents a member selected from the group consisting of: halo; hydroxy; C 1-6 alkyl(R q ) 3 ; OC 1-6 alkyl(R q ) 3 ; C 3-8 cycloalkyl(R q ) 3 ; CN; CONH 2 ; CONHC 1-6 alkyl(R q ) 3 ; CON(C 1-6 alkyl(R q ) 3 ) 2 ; NH 2 ; NHC 1-6 alkyl(R q ) 3 ; N(C 1-6 alkyl(R q ) 3 ) 2 ; CO 2 H; CO 2 C 1-6 alkyl(R q ) 3 ; C(O)C 1-6 alkyl(R q ) 3 ; aryl(R q ) 3 ; heteroaryl(R q ) 3 ; CF 3 ; SH; NO 2 ; NHSO 2 C 1-6 alkyl(R q ) 3 , NHSO 2 aryl(R q ) 3 , NHSO 2 heteroary(R q ) 3 , N(R q' )C(O)C 1-6 alkyl(R q ) 3 ; NR q' C(O)NH(C 1-6 alkyl(R q ) 3 ); C 2-4 alkenyl(R q ) 2-3 and C 2-4 alkynyl(R q ) 3 ; each R" independently represents a member selected from the group consisting of: halo; hydroxy; C 1-6 alkyl(R q ) 3 ; OC 1-6 alkyl(R q ) 3 ; C 3-8 cycloalkyl(R q ) 3 ; CN; CONH 2 ; CONHC 1-6 alkyl(R q ) 3 ; CON(C 1-6 alkyl(R q ) 3 ) 2 ; NH 2 ; NHC 1-6 alkyl(R q ) 3 ; N(C 1-6 alkyl(R q ) 3 ) 2 ; CO 2 H; CO 2 C 1-6 alkyl(R q ) 3 ; C(O)C 1-6 alkyl(R q ) 3 ; aryl(R q ) 3 ; heteroaryl(R q ) 3 ; CF 3 ; SO y C 1-6 alkyl(R q ) 3 , with y as defined above; SO 2 NH 2 ; SO 2 NHC 1-6 alkyl(R q ) 3 ; SO 2 N(C 1-6 alkyl(R q ) 3 ) 2 ; NHSO 2 C 1-6 alkyl(R q ) 3 , NHSO 2 aryl(R q ) 3 , NHSO 2 heteroary(R q ) 3 , N(R q' )C(O)C 1-6 alkyl(R q ) 3 ; NR q' C(O)NH(C 1-6 alkyl(R q ) 3 ); C 2-4 alkenyl(R q ) 2-3 and C 2-4 alkynyl(R q ) 1-3 ; each R' independently represents a member selected from the group consisting of: hydroxy; C 1-6 alkyl(R q ) 3 ; C 3-8 cycloalkyl(R q ) 3 ; OC 1-6 alkyl(R q ) 3 ; OC 3-8 cycloalkyl(R q ) 3 ; heterocyclyl(R q ) 3 ; CN; NH(R q" ); NHC 1-6 alkyl(R q ) 3 ; N(C 1-6 alkyl(R q ) 3 ) 2 ; NHC 3-8 cycloalkyl(R q ) 3 ; N(C 3-8 cycloalkyl(R q ) 3 ) 2 ; CF 3 ; C 2-4 alkenyl(R q ) 2-3 , aryl(R q ) 3 , heteroaryl(R q ) 3 ; C 2-4 alkynyl(R q ) 1-3 ; --OC(O)C 3-8 cycloalkyl(R q ) 3 ; SO 2 NH 2 ; SO 2 NHC 1-6 alkyl(R q ) 3 ; SO 2 N(C 1-6 alkyl(R q ) 3 ) 2 ; --OC(O)heterocyclyl(R q ) 3 ; CONH 2 ; CONHC 1-6 alkyl(R q ) 3 ; CON(C 1-6 alkyl(R q ) 3 ) 2 ; CONHC 3-8 cycloalkyl(R q ) 3 ; CON(C 3-8 cycloalkyl(R q ) 3 ) 2 ; C(O)aryl(R q ) 3 , C(O)heteroaryl(R q ) 3 ; R q represents a member selected from the group consisting of: R q' ; CN; CO 2 H; CO 2 C 1-4 alkyl; C(O)C 1-4 alkyl; NH(R q" );aryl(R a ) 3 ; heteroaryl(R a ) 3 ; NHC 1-4 alkyl; N(C 1-4 alkyl) 2 ; CONH 2 ; SH; S(O) y C 1-6 alkyl(R a ) 3 ; C(O)NHC 1-6 alkyl(R a ) 3 ; C(O)N(C 1-6 alkyl(R a ) 3 ) 2 ; NHC(NH)NH 2 ; -heteroalkyl(R a ) 3 ; --NHC(O)NH 2 ; ##STR115## wherein ##STR116## independently represent mono or bicyclic ring systems, non-aromatic or partially aromatic, containing from 5-10 ring atoms, 1-4 of which are N and 0-1 of which are O or S(O) y , with y equal to 0, 1 or 2, optionally containing 1-2 carbonyl groups; each R a independently represents a member selected from the group consisting of: H, C 1-6 alkyl, OC 1-6 alkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, aralkoxy, substituted aralkoxy, halo, hydroxy, CN, CONH 2 , CONHC 1-6 alkyl, CON(C 1-6 alkyl) 2 , CO 2 H, CO 2 C 1-6 alkyl, C(O)C 1-6 alkyl, phenyl, CF 3 , SH, NO 2 , SO y C 1-6 alkyl, with y as defined above; SO 2 NH 2 , SO 2 NHC 1-6 alkyl, NHSO 2 (substituted aryl), NHSO 2 (substituted heteroaryl), NHSO 2 C 1-6 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , NHC(O)C 1-6 alkyl, NHC(O)NH(C 1-6 alkyl), C 2-4 alkenyl and C 2-4 alkynyl; R q' represents H, OH, C 1-4 alkyl, --OC 1-4 alkyl, aryl or C(O)C 1-4 alkyl, and R q" represents H, OH or OC 1-4 alkyl.
23. A compound in accordance with claim 1 selected from the group consisting of: 4- 5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidine-1-carboxylic acid tert-butyl ester; 4-benzyl- 4-(4-fluorophenyl)-5-pyridin-4-yl-1H-imidazol-2-yl!-piperidine-1-carboxylic acid tert-butyl ester; 3- 5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidine-1-carboxylic acid tert-butyl ester; 4- 5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-1-acetylpiperidine; 4- 5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidine; 4- 5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-1-methyl-piperidine; 4- 5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-1-benzyl-piperidine; 4- 5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-1-ethyl-piperidine; 4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidine; 4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-1-methyl-piperidine; 2-(4-{4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidin-1-yl}-butyl)-isoindole-1,3-dione; 2-(5-{4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidin-1-yl}-pentyl)-isoindole-1,3-dione; 2-(6-{4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidin-1-yl}-hexyl)-isoindole-1,3-dione; 4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-1-benzyl-piperidine; 2-(5-{4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidin-1-yl}-pentyl)-2,3-dihydro-isoindol-1-one; 4-(4-{4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidin-1-yl}-ethyl)-pyridine; 2-(5-{4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidin-1-yl}-pentyl)-1,1-dioxobenzo d!isothiazol-3-one; 2-(4-{4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidin-1-yl}-butyl)-1,1-dioxobenzo d!isothiazol-3-one; 4- 5-(3-hydroxyphenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-1-methyl-piperidine 3- 5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidine: 3- 5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-1-methyl-piperidine; 4- 5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-1,4-dimethyl-piperidine; 4-benzyl- 4-(4-fluorophenyl)-5-pyridin-4-yl-1H-imidazol-2-yl!-piperidine-1-carboxylic acid tert-butyl ester; 4-benzyl- 4-(4-fluorophenyl)-5-pyridin-4-yl-1H-imidazol-2-yl!-piperidine; 2-amino-1-{5- 4-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidin-1-yl}-ethanone; 4-{5-(3,4-dichlorophenyl)-2- 1-(2-phenylethyl)-piperidin-4-yl!-1H-imidazol-4-yl}-pyridine; 4-{5-(3,4-dichlorophenyl)-2- 1-(3-phenylpropyl)-piperidin-4-yl!-1H-imidazol-4-yl}-pyridine; 2-(6-{4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidin-1-yl}-hexyl)-1,1-dioxobenzo d!isothiazol-3-one; 2-(3-{4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidin-1-yl}-propyl)-1,1-dioxobenzo d!isothiazol-3-one; 4-(5-{4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidin-1-yl-methyl}-imidazol-1-yl-methyl)-benzonitrile; 4- 2- 1-(4-benzyloxybenzyl)-piperidin-4-yl-5-(3,4-dichlorophenyl)-1H-imidazol-4-yl-pyridine; 4- 4-fluorophenyl)-3-pyridin-yl-1H-imidazol-2-yl!-1-acetyl-piperidine; 3- 4-fluorophenyl)-3-pyridin-yl-1H-imidazol-2-yl!-1-acetyl-piperidine; and 2-(3-{4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-piperidin-1-yl}-propyl)-isoindole-1,3-dione, or a pharmaceutically acceptable salt thereof.
24. A compound in accordance with claim 1 selected from the following table: __________________________________________________________________________
No.
Compound
__________________________________________________________________________
##STR117##
2
##STR118##
3
##STR119##
4
##STR120##
5
##STR121##
6
##STR122##
7
##STR123##
8
##STR124##
9
##STR125##
10
##STR126##
11
##STR127##
12
##STR128##
13
##STR129##
14
##STR130##
15
##STR131##
16
##STR132##
17
##STR133##
18
##STR134##
19
##STR135##
20
##STR136##
21
##STR137##
22
##STR138##
23
##STR139##
24
##STR140##
25
##STR141##
26
##STR142##
27
##STR143##
28
##STR144##
__________________________________________________________________________
or a pharmaceutically acceptable salt thereof.
25. A compound in accordance with claim 1 selected from the group consisting of: 4- 5-(3,4-dichlorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!piperidine-1-carboxylic acid benzyl ester; 4- 5-(3-methoxyphenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!piperidine-1-carboxylic acid tert-butyl ester; 4- 5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl!-4-methylpiperidine-1-carboxylic acid tert-butyl ester; 4- 1-propyl-5-pyridin-4-yl-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl!piperidine-1-carboxylic acid benzyl ester; 4- 1-hydroxy-5-(2-fluoropyridin-4-yl)-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl!piperidine-1-carboxylic acid benzyl ester; 4- 5-(2-fluoropyridin-4-yl)-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl!piperidine-1-carboxylic acid benzyl ester; 4- 5-(2-fluoropyridin-4-yl)-1-methyl -4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl!-piperidine-1-carboxylic acid benzyl ester and (S)-4- 5-(2-(1-Phenylethylamino)pyridin-4-yl)-1-methyl-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl!-piperidine-1-carboxylic acid benzyl ester.
26. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
27. A pharmaceutical composition which is produced by combining a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.
28. A method of treating cancers that respond to inhibition to RAF kinase which comprises administering to a mammalian patient in need of such treatment a compound in accordance with claim 1 in an amount which is effective to treat said cancers.
29. A method of treating a cytokine mediated disease in a mammal, comprising administering to a mammalian patient in need of such treatment an amount of a compound as described in claim 1 in an amount which is effective to treat said cytokine mediated disease.
30. A method of treating inflammation in a mammalian patient in need of such treatment, which is comprised of administering to said patient an anti-inflammatory effective amount of a compound as described in claim 1.
31. A method of treating osteoporosis in a mammalian patient in need of such treatment, which is comprised of administering to said patient an amount of a compound as described in claim 1 which is effective to treat osteoporosis.
32. A method of treating bone resorption in a mammalian patient in need of such treatment, which is comprised of administering to said patient an amount of a compound as described in claim 1 which is effective to treat bone resorption.
33. A method of treating Crohn's disease in a mammalian patient in need of such treatment which is comprised of administering to said patient an amount of a compound as described in claim 1 which is effective to treat Crohn's disease.Cited by (0)
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